Obesity increases both the incidence and mortality of numerous types of cancer. A recent retrospective study found that children who are obese at the time of diagnosis of high-risk acute lymphoblastic leukemia (ALL) have a 50% increased risk of relapse compared to lean children. This higher mortality may be due to a direct effect of obesity on the leukemia itself, perhaps mediated by some adipocyte-derived hormone or cytokine. Alternatively, it may be an effect of obesity to confound the leukemia treatment, possibly due to altered pharmacokinetics of chemotherapeutic agents. Given the high prevalence of both ALL and obesity, it is imperative that we investigate the link between these two conditions. Therefore, we have developed mouse models of obesity and ALL. We have found that obese mice with ALL are more likely to relapse after treatment with vincristine, even when it is dosed proportional to body weight. Also, we have in vitro data demonstrating that adipocytes have multiple effects to impair chemotherapy of ALL: they secrete as yet unidentified factors which cause ALL resistance to dexamethasone, and they concentrate vincristine out of the extracellular environment, making it inaccessible to the ALL cells. The present studies are designed to build on these results. In our first Aim, we will use a proteomics approach to identify the adipocyte-derived factor(s) responsible for causing dexamethasone resistance. We will also investigate the regulation of their synthesis and secretion, and their mechanism(s) of action on leukemia cells. In our second Aim, we will perform pharmacokinetics experiments in obese mice with vincristine and dexamethasone to quantify how obesity alters the leukemia exposure to these agents. Finally, in our third Aim, we will use a novel model of diet-induced obesity in an immunosuppressed mouse, the NOD/SCID IL2R 3c -/- mouse, to explore the effects of obesity on human leukemia cells in vivo. With this model we will also investigate how leukemia infiltration into adipose tissue may lead to resistance to therapy. These studies will increase our understanding of leukemia and its relation to obesity, and they have the potential to change the way we treat cancer in our increasingly overweight population. They will also provide insight into the leukemia cell niche and identify potential targets for ALL glucocorticoid resistance. These studies could lead directly to improvements in cancer treatment and saved lives in both lean and overweight children and adults. PUBLIC HEALTH RELEVANCE: Overweight children who get leukemia, the most common type of cancer in children, have a 50% higher chance of having the cancer come back after treatment. The present studies will examine the reasons why being overweight makes leukemia more difficult to cure and investigate ways to reverse these effects. Since populations around the world are becoming more obese, finding out how obesity affects cancer outcome and treatment will have a significant impact on the development of strategies to more effectively treat these cancers.